Prostaglandin derivatives and process for preparing the same

ABSTRACT

Prostaglandin derivatives corresponding to the general formula: ##STR1## wherein R 1  represents hydrogen, methyl or ethyl, R 2 , R 3  and R 4 , which are the same or different, each represent hydrogen or methyl and R is selected from the groups consisting of: ##STR2## in which R 5  represents hydrogen, methyl or ethyl, R 6  represents methyl, ethyl or acetyl and R 7  and R 8 , when they are different, each represent hydrogen or a branched- or straight-chain alkyl group having from 1 to 7 carbon atoms or R 7  and R 8 , when they are identical, each represent hydrogen or a straight-chain alkyl group having from 1 to 3 carbon atoms with the provisos that: 
     When both R 7  and R 8  represent hydrogen, R 5  is methyl or ethyl, 
     When R 5  represents methyl and R 2 , R 3 , R 4 , R 7  and R 8  all represent hydrogen then R 1  is ethyl, 
     The said prostaglandin derivatives being in the form of a mixture of isomers or of an individual isomer. They are useful in the treatment of pathological states which affect the respiratory system.

This invention relates to the prostaglandins and is concerned with novelcompounds related in structure to prostaglandin E₁ which has thestructural formula: ##STR3## and to a process for preparing the saidnovel compounds.

Prostaglandin E₁ is normally abbreviated to "PGE₁ ". In accordance withcommon usage the formula of PGE₁ can also be written as: ##STR4##

The compounds with which the present invention is concerned are thosecorresponding to the general formula: ##STR5## wherein R₁ representshydrogen, methyl or ethyl, R₂, R₃ and R₄, which are the same ordifferent, each represent hydrogen or methyl and R is selected from thegroups consisting of: ##STR6## in which R₅ represents hydrogen, methylor ethyl, R₆ represents methyl, ethyl or acetyl and R₇ and R₈, when theyare different, each represent hydrogen or a branched- or straight-chainalkyl group having from 1 to 7 carbon atoms or R₇ and R₈, when they areidentical, each represent hydrogen or a straight-chain alkyl grouphaving from 1 to 3 carbon atoms with the provisos that:

when both R₇ and R₈ represent hydrogen, R₅ is methyl or ethyl.

when R₅ represents methyl and R₂, R₃, R₄, R₇ and R₈ all representhydrogen then R₁ is ethyl.

One class of compounds falling within the definition of formula Iconsists of the prostaglandin derivatives represented by the saidformula I wherein R₁ represents hydrogen, methyl or ethyl, R₂, R₃ and R₄each represent hydrogen or methyl and R is selected from the groups Aand B wherein R₅ represents hydrogen, methyl or ethyl, R₆ representsmethyl, ethyl or acetyl and R₇ and R₈, when they are different, eachrepresent hydrogen or a branched-or straight-chain alkyl group havingfrom 1 to 7 carbon atoms or R₇ and R₈, when they are identical, eachrepresent hydrogen or a straight- chain alkyl group having from 1 to 3carbon atoms with the proviso that at least one of the groups R₂, R₃ andR₄ is methyl.

A pharmacologically preferred class of compounds with which theinvention is concerned consists of the prostaglandin derivatives offormula I wherein R₁ represents hydrogen, methyl or ethyl, R₂, R₃ and R₄each represent hydrogen or methyl and R is selected from the groups Aand B wherein R₅ represents hydrogen, methyl or ethyl, R₆ representsmethyl or acetyl and R₇ and R₈, which are identical, each representhydrogen or methyl with the provisos that:

when both R₇ and R₈ represent hydrogen, R₅ is methyl or ethyl,

when R₅ represents methyl and R₂, R₃, R₄, R₇ and R₈ all representhydrogen, then R₁ is ethyl,

when R₆ represents methyl and R₂, R₃, R₄, R₇ and R₈ all representhydrogen, then R₁ is methyl.

Examples of compounds of this class are:

Dl-Φ-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-methyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15 methyl-PGE₁ ethyl ester.

Dl-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-ethyl-PGE₁ ethyl ester.

Dl-ω-carboxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-ethyl-PGE₁.

Dl-ω-carboethoxy-1-hexyl-5-(3'-acetoxy-1'-octen(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-0-acetyl-PGE₁ ethyl ester.

Dl-ω-carboxy-1-hexyl-5-(3'-acetoxy-1'-octen-(E)-yl)-2-pyrrolidinone orDL-8-aza-11-deoxy-15-0-acetyl-PGE₁.

Dl-ω-carbomethoxy-1-hexyl-5-(3'-methoxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-0-methyl-PGE₁ methyl ester.

Dl-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ ethyl ester.

Dl-ω-carboxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL=8-aza-11-deoxy-16,16-dimethyl-PGE₁.

Dl-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-2-methyl-8-aza-11-deoxy-PGE₁ ethyl ester.

Dl-1-(6'-carboxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-2-methyl-8-aza-11-deoxy-PGE₁.

Dl-1-(6'-carboethoxy-2'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-6-methyl-8-aza-11-deoxy-PGE₁ ethyl ester.

Dl-1-(6'-carboxy-2'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-6-methyl-8-aza-11-deoxy-PGE₁.

Dl-1-(6'-carboethoxy-3'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-5-methyl-8-aza-11-deoxy-PGE₁ ethyl ester.

Dl-1-(6'-carboxyl-3'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-5-methyl-8-aza-11-deoxy-PGE₁.

The compounds of formula I possess isomeric centres and thus can beproduced as optical isomers, position isomers or mixtures of theseisomers. The mixtures of these isomers can be resolved, if desired, atappropriate stages by methods known to those skilled in the art toobtain the respective individual isomers.

It is to be understood that these isomers as well as mixtures thereofare included within the scope of the present invention.

The compounds of formula I wherein R₁ represents hydrogen, R₂, R₃ and R₄have the meaning cited therein and R represents the group A or the groupB wherein R₆ represents methyl or ethyl can be prepared bysaponification in an alcoholic medium such as methanol, of an estercorresponding to the general formula: ##STR7## wherein R₂, R₃ and R₄have the same meaning as in formula I, R₉ represents a branched- orstraight-chain alkyl group having from 1 to 7 carbon atoms and R₁₀ isselected from the groups consisting of the group A in formula I and thegroup: ##STR8## in which R₇ and R₈ have the same meaning as in formula Iand R₁₁ represents methyl or ethyl, the saponification being effected bymeans of an alkali, for example sodium hydroxide, followed by hydrolysisof the resulting alkali metal salt of the compound of formula II bymeans of a strong acid, for example hydrochloric acid, to form therequired compound of formula I.

The compound of formula I wherein R₁ represents hydrogen, R₂, R₃ and R₄have the meaning cited therein and R represents the group B wherein R₆represents acetyl, can be obtained by refluxing an acid of the generalformula: ##STR9## in which R₂, R₃, R₄, R₇ and R₈ have the same meaningas in formula I with aqueous acetic acid, which provides the requiredcompound of formula I.

The esters of formula I can be obtained by various methods according totheir chemical structure. Thus, in accordance with the presentinvention, the esters of formula I wherein R₂, R₃ and R₄ have themeaning cited therein, R₁ represents methyl or ethyl and R representsthe group A in which R₅, R₇ and R₈ have the meaning given, can beobtained from a pyrrolidinone derivative of the general formula:##STR10## wherein R₂, R₃, R₄, R₇ and R₈ have the same meaning as informula I an R₁₂ represents methyl or ethyl:

(a) When R₅ represents hydrogen by reduction with a suitable reducingagent, for example sodium borohydride in a inert medium, for exampledimethoxyethane. The reduction in question can be carried out at atemperature between 0° and +5° C and preferably at 0° C.

(b) When R₅ represents methyl or ethyl, be treatment in an anhydrousether, such as, for example, ethyl ether or tetrahydrofuran, with thebromide or iodide of methyl or ethyl magnesium, and subsequenthydrolysis of the resulting complex with, for example, a saturatedaqueous solution of ammonium chloride to obtain the required ester offormula I. The treatment of the ketone in question of formula IV will beeffected at a temperature between -15° C and 0° C, to obtain therequired ester of formula I wherein R₅ represents methyl and at atemperature between -15° C and -5° C, preferably at -5° C, to obtain therequired ester of formula I wherein R₅ represents ethyl. The esters offromula I wherein R₂, R₃ and R₄ have the meaning cited therein, R₁represents methyl or ethyl and R represents the group B, in which R₇ andR₈ have the meaning given, can be prepared as follows:

(c) When R₆ represents methyl or ethyl, be reacting at room-temperatureand in an anhydrous ether, such as, for example anhydrous ethyl ether anacid of the general formula III hereabove, with methyl or ethyl iodidein the presence of an alkali metal hydride such as, for example, sodiumhydride to obtain the ester of formula I wherein R₁ and R₆ are identicalwhich, if desired, can be saponified by means of an alkali metalhydroxide, for example sodium hydroxide to obtain the corresponding acidwhich is then re-esterified with ethanol or methanol in an acid medium,for example sulphuric acid, to obtain the required ester wherein R₁ andR₆ are different.

(d) When R₆ represents acetyl, by reacting, in an appropriate solvent,such as, for example pyridine or methylene chloride and atroom-temperature, an ester of the general formula: ##STR11## wherein R₂,R₃, R₄, R₇ and R₈ have the same meaning as in formula I and R₁₂represents methyl or ethyl, with acetyl chloride or acetic anhydridewhich provides the required ester of formula I.

As an alternative procedure, the esters of formula I, wherein Rrepresents the group A in which R₇ and R₈ represent the substituentsrecited above and R₅ represents hydrogen, can be obtained by esterifyingin an inert medium such as, for example methylene chloride and atroom-tempreature an acid of the general formula III with eitherdiazomethane of diazoethane which provides the required methyl or ethylester.

Among the starting-compounds represented by formula II those in which R₉represents methyl or ethyl are also compounds included within the scopeof formula I for which a process of preparation is described hereabove.The other esters of formula II can all be prepared in accordance withthe aforesaid method given for the preparation of the methyl and ethylesters of both formulae I and II.

The starting-compounds corresponding to formulae III and V are productsincluded within the scope of formula I for which a process ofpreparation is described hereabove. With regard to the compounds offormula IV, these can be prepared by submitting a5-carboxaldehyde-2-pyrrolidinone derivative of the formula: ##STR12##wherein R₂, R₃ and R₄ have the same meaning as in formula I and R₁₂ hasthe same meaning as in formula IV, to a Wittig reaction with a dimethyl2-oxo-n-heptylphosphonate derivative of the formula: wherein R₇ and R₈have the same meaning as in formula I so as to obtain the correspondingketone.

The compunds of formula VI wherein R₂, R₃ and R₄ each represent hydrogenare known compunds having been described together with their process ofpreparation in French Pat. No. 2,304,340. The other compounds of formulaVI can be prepared in accordance with the method set out in the saidFrench Patent.

As regards the phosphorus-containing compunds of formula VII, these canbe obtained by first reacting an appropriate ethyl hexanoate derivativewith dimethyl methylphosphonate in the presence of butyllithium. Theethyl hexanoate derivatives in question are either known compounds orcan be prepared in accordance with known procedures.

The compounds of the invention have been found to possess valuablepharmacological properties. Most of these properties are characteristicof the natural prostaglandins in general and of the prostaglandin E₁,also known as PGE₁, in particular. For example, the prostaglandinderivatives of the invention have shown that they exert a contractingaction on the smooth intestinal and uterine muscles, a hypotensive and avasodilatory effect as well as an inhibiting action on gastric secretionand on platelet aggregation. It has also been found that theprostaglandin derivatives of the invention have, in addition to theirother properties, a bronchodilatory activity capable of being usedparticularly in the treatment of asthma and pathological statesaffecting the respiratory system.

Consequently, another object of the invention is to provide a method oftreating, in a human or animal organism in need of such treatment, thevarious affections which are favourably influenced by the action of PGE₁and, in particular, asthma or pathological states affecting therespiratory system, which method comprises administering to saidorganism an effective amount of at least one compound of formula I inthe form of a mixture of isomers or of an active isomer, advantageouslypresented as a pharmaceutical or veterinary composition.

A further object of the invention is, therefore, a pharmaceutical orveterinary composition containing as essential active ingredient atleast one compound of formula I in the form of a mixture of isomers orof an active isomer in association with a non-toxic carrier or excipienttherefor.

Likewise, the invention also encompasses a method for preparingpharmaceutical and veterinary compositions whereby at least one compoundof formula I in the form of a mixture or isomers or of an active isomeris associated with a non-toxic carrier or excipient therefor.

For several years, the prostaglandins have aroused particular interestat pharmacological and therapeutic levels. They are, in fact, naturalcompounds which are very widely distributed in the tissues of mammalsand of which several have been isolated from human seminal liquids.

The prostaglandins have a very wide range of activity, which seems toresult from their influence on the synthesis of 3', 5'-cyclic adenosinemonophosphate (cyclic AMP).

According to their chemical configuration, they have variouspharmacological actions such as hypertensive, hypotensive oranti-ulcerogenic activity or, depending on the part of the bodyconcerned, a stimulating or relaxing effect upon smooth muscle, all ofwhich actions become apparent a very closely related doses.

This lack of specificity on the part of natural prostaglandins ismoreover responsible for most of the secondary effects which they canproduce.

Of the natural prostaglandins, the prostaglandin referred to above andknown as PGE₁ seems to be amongst the most active, as has been shown inChimie Therapeutique 1, 34 (1969). PGE₁ is for example capable ofstimulating the intestinal and uterine smooth muscle, of causingvasodilation and bronchodilation, of reducing gastric secretion andinhibiting platelet aggregation at infinitesimal doses of the order of ananogram.

However PGE₁ has certain disadvantages which are inherent in the naturalprostaglandins, because of its lack of specificity. For example, PGE₁,by its spasmogenic action on the alimentary canal will produce certainside-effects such as nausea, vomiting and diarrhoea.

It is therefore desirable to have available a synthetic prostaglandinwhich shows a greater specificity as regards therapeutic action, therebyeliminating certain disadvantages of PGE₁, especially those referred toabove.

The compounds of the invention achieve this objective. In actual fact,pharmacological tests carried out with these compounds and forcomparison purposes with PGE₁ have shown that compounds of formula I, inthe same way as PGE₁, contact the smooth intestinal and uterine muscles,dilate the blood vessels as well as the bronchi, decrease arterialpressure and inhibit gastric secretion. However the compounds of theinvention function in a much more specific manner than PGE₁ at thebronchial level and are generally more active as bronchodilatory agentsthan PGE₁.

The compounds of the invention are thus capable of being usedtherapeutically in the treatment of pathological states which affect therespiratory system, and especially asthma, with substantially none ofthe secondary effects previously referred to in respect of PGE₁.

Derivatives of prostaglandin E₁ having a nitrogen atom in the 8-positionare already known.

In French Pat. No. 2,304,340 there are described DL-8-aza-11-deoxy-PGE₁and esters thereof which are presented as possessing a contractingaction on the smooth intestinal and uterine muscles, a vasodilatoryeffect as well as an inhibiting action on gastric secretion.Furthermore, DL-8-aza-11-deoxy-PGE₁ and esters thereof, were found topossess a bronchodilatory action which is much more specific than thatof PGE₁.

However, it was surprisingly discovered that the compounds of theinvention are generally more active than DL-8-aza-11-deoxy-PGE₁.

Furthermore, it has also been found that the bronchodilatory action ofthe compounds of the invention is still more specific than that ofDL-8-aza-11-deoxy-PGE₁.

Consequently, when used therapeutically in the treatment of pathologicalstates affecting the respiratory system, the compounds of the inventionwill be likely to present less undesirable side-effects thanDL-8-aza-11-deoxy-PGE₁.

Independently of their pharmacological utility, the 2-pyrrolidinonederivatives of the invention have in addition certain advantages overPGE₁, particularly as regards their preparation. PGE₁, being a naturalproduct, can be obtained for example by extraction from naturalmaterials, especially from vesicular glands of sheep, lungs of pigs oreven from human seminal plasma. It is evident that such sources ofsupply will only permit this product to be obtained in limitedquantities and with the use of expensive equipment, which will have theeffect of increasing the cost of the product to a substantial degree.

Furthermore, production of PGE₁ by a synthetic route cannot be achievedwithout considerable difficulty owing to the several centres ofasymmetry present in the molecule with the result that the number ofstages in the preparation of the compound is multiplied with aconsequent increase in the manufacturing cost.

The synthesis of the compounds of formula I in accordance with theinvention substantially avoids these difficulties.

Their simpler chemical structure which, in fact, eliminates theasymmetry at the 8 and 11 carbon atom positions of PGE₁, has the resultof facilitating chemical synthesis. Furthermore, the starting-productsrequired for the preparation of the compounds of the invention can beeasily obtained, and hence it will be possible to prepare the compoundsof the invention in much larger quantities than is possible whenstarting from natural tissues as in the case of PGE₁.

These important advantages inherent in the preparation of the compoundsaccording to the invention will contribute to their bring shownpreference over PGE₁.

The results of a number of pharmacological tests carried out with thefollowing compounds of the invention are set out below:

Dl-8-aza-11-deoxy-16,16-dimethyl-PGE₁ (Compound 1)

Dl-8-aza-11-deoxy-15-ethyl-PGE₁ (Compound 2)

Dl-8-aza-11-deoxy-15-0-acetyl-PGE₁ (Compound 3)

Dl-8-aza-11-deoxy-15-methyl-PGE₁ ethyl ester (Compound 4)

Dl-2-methyl-8-aza-11-deoxy-PGE₁ (Compound 5)

These pharmacological tests, carried out in comparison with PGE₁ andDL-8-aza-11-deoxy-PGE₁, show the markedly specific nature of the actionof the compounds of formula I on the bronchial tubes.

In each of these trials, the compound tested was employed in the form ofethanolic solutions diluted with distilled water.

I. Spasmogenic action on isolated intestine or uterus

For this purpose the MAGNUS technique [Arch. Ges. Physiol. 102, 123(1904)] was employed.

It was found that, on the ileum of a guinea pig, Compounds 1, 2, 3, 4and 5 of the invention do not produce any spasm at a dose of 10⁻³ g/mlof bath, whereas when using PGE₁ and DL-8-aza-11-deoxy-PGE₁ doses of 10⁻6g/ml and 5 × 10⁻³ g/ml respectively are sufficient to obtain spasms ofequal intensity.

This means that the spasmogenic properties of the compounds of theinvention are extremely weak and are at least one thousand times weakerthan those of PGE₁ and at least five times weaker than those ofDL-8-aza-11-deoxy-PGE₁.

Used on the uterus of a rat, which had been blocked prior to the oestralcycle by means of stilboestrol, it was found that PGE₁ contracts thisorgan in an intense and regular manner at a dose of 0.3 × 10⁻⁵ g/ml,whereas it is necessary to introduce into the bath a dose 200 timeslarger, i.e. 0.6 × 10⁻³ g/ml of DL-8-aza-11-deoxy-PGE₁ in order toobtain an equivalent spasm. As against this, Compounds 1,3, 4 and 5 aretotally inactive at a dose of 10⁻³ g/ml as spasmogenic agents.

II. Cardiovascular action

The effect of different doses of the compounds of the invention, of PGE₁and of DL-8-aza-11-deoxy-PGE₁ on systolic arterial pressure, diastolicarterial pressure and cardiac frequency was investigated in theconventional manner in dogs.

Administered intraveneously, in a dose of 0.5 to 1μg/kg, PGE₁immediately causes a systemic arterial hypotension having an effect onboth the systolic and the diastolic pressure. The mean pressure isreduced, depending on the animal, by between 5% and 21% of its initialvalue, while a moderate sinusal tachycardia becomes apparent.

As regards, DL-8-aza-11-deoxy-PGE₁, it was observed that, administeredintravenously and in doses between 5 and 50 μg/kg this compound producesthe same effects as PGE₁ on the cardiovascular system.

With respect to the compounds of the invention, it was observed that atdoses below 100 μg/kg of Compound 1, 50 μg/kg of Compound 2, 300 μg/kgof Compound 3 and 200 μg/kg of Compound 5 no inhibitory effect appearson cardiac frequency and arterial pressure.

When adminisrtered in the femoral artery of dogs in a dose of 0.01μg/kg, PGE₁ increases the arterial flow by +173%, while 1μg/kg ofDL-8-aza-11-deoxy-PGE₁ causes a variation of +115% of the initial flow.

With respect to the compounds of the invention, it was observed that novariation of the arterial flow occurred after the administration by thesame route of 50 γ/kg of Compound 1, 100 γ/kg of Compound 2, 50 γ/kg ofCompound 3 and 100 γ/kg of Compound 5.

At doses of 100 γ/kg of Compound 1, 300 γ/kg of Compound 2, 100 γ/kg ofCompound 3 and 100 γ/kg of Compound 5, a slight variation of thearterial flow was registered but it was without any statisticalsignificance. These results show that the compounds of the invention aremuch less active on the cardiovascular system that PGE₁ andDL-8-aza-11-deoxy-PGE₁.

III. Bronchodilatory activity on the guinea-pig.

For this purpose the technique developed by KONZETT & ROSSLER (Arch.Exp. Path. Pharmakol., 1940, 195, 71-74) was used, the spasm-promotingagent being acetylcholine.

The results obtained with compounds of the invention in comparison withPGE₁ and DL-8-aza-11-deoxy-PGE₁ are given in the following Table.

The percentages of reduction of the bronchospasm were calculated atdifferent times after the intravenous administration of 10 μg/kg of thecompound under study.

                  TABLE                                                           ______________________________________                                                         % of reduction                                               Compound         of the bronchospasm after:                                   ______________________________________                                                          5 minutes                                                   Compound 1       51                                                           Compound 3       51                                                           Compound 4       54                                                           DL-8-aza-11-deoxy-PGE.sub.1                                                                    43                                                           PGE.sub.1        37                                                                            10 minutes                                                   Compound 2       28                                                           Compound 3       34                                                           Compound 4       21                                                           DL-8-aza-11-deoxy-PGE.sub.1                                                                    28                                                           PGE.sub.1        6                                                                             15 minutes                                                   Compound 2       5                                                            Compound 3       6                                                            Compound 4       6                                                            DL-8-aza-11-deoxy-PGE.sub.1                                                                    0                                                            PGE.sub.1        0                                                            ______________________________________                                    

These results show that the compounds are more active than PGE₁ andgenerally more active than DL-8-aza-11-deoxy-PGE₁.

Furthermore, judging by the overall pharmacological results, it appearsthat the bronchodilatory action of the compounds of the invention ismore specific than that of PGE₁ and DL-8-aza-11-deoxy-PGE₁.

It will also be noted that the compounds are still active asbronchodilatory agents after PGE₁ and DL-8-aza-11-deoxy-PGE₁ have ceasedto exert their effect.

The pharmaceutical and veterinary compositions of the invention can bemade up in any form which is suitable for their administration in humanand veterinary therapy. For ease of administration the composition willnormally be made up in a dosage unit form appropriate to the desiredmode of administration, for example, a compressed tablet for perlingualadministration, a pill, a powder, a capsule, a syrup for oraladministration, a suspension for oral or aerosol administration, asuppository for rectal administration, a cream or an ointment fortopical or local administration or a sterile solution or suspension forparenteral administration.

The therapeutic compositions of the invention will be prepared inaccordance with known techniques by associating at least one compound ofthe invention with an appropriate diluent or excipient and then ifrquired making up the resulting admixture in the desired dosage unitform. Examples of suitable diluents and excipients are distilled water,ethanol, talc, magnesium stearate, starch and cocoa butter.

The range of active substance used may, for example, be 0.5 μg to 3000μg daily in 1 to 60 aerosol inhalations for asthma or other affectionsof the respiratory system.

The following Examples illustrate the preparation of the compounds ofthe invention.

In these Examples, the analytical results obtained from nuclear magneticresonance spectra (N.M.R.) comprise the following abbreviations, whichindicate:

δ or chemical displacement indicates the dierence between the fieldforces at which signals are obtained for the nuclei of the same type,such as the proton, but situated in a different molecular environment

ppm = part per million

Cdcl₃ = deuterium-containing chloroform, used as reference and assolvent.

In addition, the Rf values indicated in the following Examples weredetermined by thin layer chromatography using a 20/80 acetone/methylenechloride mixture as solvent.

EXAMPLE 1 Preparation ofDL-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-methyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-methyl-PGE₁ ethyl ester

A solution of methyl magnesium iodide was first prepared from 0.213 g(0.0015 mol) of methyl iodide, 10 ml of anhydrous ethyl ether and 0.036g (about 0.0015 mol) of magnesium turnings. This mixture was cooled to0° C and then 0.365 g (0.001 mol) was added ofDL-ω-carboethoxy-1-hexyl-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinonedissolved in 10 ml of anhydrous ethyl ether. The reaction medium wasstirred at 0° C for 4 hours and then 5 ml of a saturated aqueoussolution of ammonium chloride were added. The mixture was stirred atroom-temperature for 30 minutes and then extracted by means of 50 ml ofether. The organic phase was dried and concentrated under vacuum.

In this manner, there was obtained 0.500 g ofDL-8-aza-11-deoxy-15-methyl-PGE₁ ethyl ester in the form of a paleyellow oil. Yield: 78% Rf = 0.62 and 0.66.

I.R. Spectrum (CHCl₃): OH at 3440 cm⁻¹,

CO (ester) at 1730 cm⁻¹,

CO (amide) at 1680 cm⁻¹,

CH = CH at 1635 cm⁻¹.

N.M.R. Spectrum (CDCl₃): δ = 0.9 ppm (CH₃),

= 1.25 ppm (CH₃ in the 15-position),

= 1.3 ppm (CH₃ ester),

= 2.7 ppm (OH),

= 4.1 ppm (CH₂ ester),

= 6 to 7 ppm ##STR13##

EXAMPLE 2 Preparation ofDL-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-ethyl-PGE₁ ethyl ester

A solution of 0.163g (0.0015 mol) of ethyl bromide and 0.036g (0.0015mol) of magnesium turnings in 10ml of anhydrous ether was cooled to -5°C and treated, at this temperature, for 4 hours by 0.365g ofDL-ω-carboethoxy-1-hexyl-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinonedissolved in 10ml of dry ether. To this reaction medium 5ml of asaturated solution of ammonium chloride was added. The mixture wasallowed to stand for 30 minutes and then extracted with ether. Theorganic phase was washed with 50ml of water and then dried andconcentrated.

In this manner, there was obtained the DL-8-aza-11-deoxy-15-ethyl-PGE₁ethyl ester in a yield of 64% Rf: 0.20 and 0.41.

I.R. Spectrum (CHCl₃): OH at 3440 cm⁻¹,

CO (ester) at 1720 cm⁻¹,

CO (amide) at 1675 cm⁻¹.

N.M.R. Spectrum (CDCl₃): δ = 0.9 ppm (CH₃ in the 15-psoition and CH₃ inthe 20-position)

= 4.15 ppm ##STR14## = 5.6 ppm (CH=CH).

Preparation ofDL-ω-carboxy-1-hexyl-5-(3'-hydroxy-3'-ehtyl-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-ethyl-PGE₁

A solution of 0.200g (about 0.0005 mol) ofDL-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinonein 15ml of methanol was treated with 10ml of 0.5N-sodium hydroxide atroom-temperature for 12 hours. The reaction medium was then extractedwith methylene chloride and the aqueous phase was acidified by means of1N-hydrochloric acid and extracted with methylene chloride. The organicfraction was then dried and concentrated.

In this manner, there was obtained 0.120g ofDL-8-aza-11-deoxy-15-ethyl-PGE₁ in the form of a colourless gel. Yield:56%. Rf = 0.11 and 0.13.

I.R. Spectrum (CHCl₃): OH and COOH at 2500-3500 cm⁻¹,

CO (acid) at 1710 cm⁻¹,

CO (amide) at 1660 cm⁻¹.

N.M.R. Spectrum (CDCl₃): δ = 0.85 ppm (CH₃ in the 15-position and CH₃ inthe 20-position)

= 4.45 ppm (OH and COOH)

= 5.6 ppm (CH═CH).

EXAMPLE 4 Preparation ofDL-ω-carboethyoxy-1-hexyl-5-(3'-acetoxy-1'-octen-(E)-yl-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-0-acetyl-PGE₁ ethyl ester

To a solution of 0.183g (0.0005 mol) ofDL-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinonein 10ml of anhydrous methylene chloride was added 1.5ml of dry pyridine.The solution was cooled to 0° C and a solution of 1ml of acetyl chloridein 5ml of anhydrous methylene chloride was added drop-by-drop. Themixture was stirred at room-temperature for 12 hours and then pouredinto iced water. After extraction with 50ml of methylene chloride, theorganic fraction was washed several times with water. The methylenechloride solution was filtered on a silica gel column and the filtratewas concentrated. After washing of the residue with hexane to remove thetraces of pyridine, the traces of solvent were eliminated under vacuum.

In this manner, there was obtained 0.180g ofDL-8-aza-11-deoxy-15-0-acetyl-PGE₁ ethyl ester in the form of acolourless gel. Yield: 88%. Rf = 0.65.

I.R. Spectrum (CHCl₃): CO(esters) at 1730 cm⁻¹,

CO(amide) at 1670 cm⁻¹,

--O--C-- at 1250 cm⁻¹.

N.M.R. Spectrum (CDCl₃)δ: = 0.9 ppm (CH₃),

= 2.05 ppm (-- O--COCH₃),

= 4.15 ppm (CH₂ --O--CO),

= 5.3 ppm (--CH--O--CO),

= 5.6 ppm (CH═CH).

EXAMPLE 5 Preparation ofDL-ω-carboxy-1-hexyl-5-(3'-acetoxy-1'-octen-(E)-yl)-1-pyrrolidinone orDL-8-aza-11-deoxy-15-O-acetyl-PGE₁

A mixture of 0.169g (0.0005 mol) ofDL-ω-carboxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinone,10ml of acetic acid and 10ml of distilled water was heated under refluxfor 24 hours. The water and the acetic acid were eliminated under vacuumin the presence of benzene. This operation was repeated several times.After that, the residue was washed several times with hexane and thetraces of hexane were eliminated under vacuum.

In this manner, there was obtained 0.150g ofDL-8-aza-11-deoxy-15-O-acetyl-PGE₁. Yield: 63%. Rf = 0.22.

I.R. Spectrum (film) : CH₃ COO at 1250 cm⁻¹,

CO (amide) at 1670 cm⁻¹,

CO (acid) at 1715 cm⁻¹.

N.M.R. Spectrum (CDCl₃)δ: = 2.0 ppm (CH₃ CO),

= 5.6 ppm (CH═CH),

= 7.4 ppm (COOH).

EXAMPLE 6 Preparation ofDL-ω-carbomethoxy-1-hexyl-5-(3'-methoxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-15-0-methyl-PGE₁ methyl ester

To a suspension of 0.050g of sodium hydride previously washed withhexane in 10ml of anhydrous ether, was added 0.169g (about 0.0005 mol)of DL-ω-carboxy-1-hexyl-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinonedissolved in 20ml of anhydrous ether. The reaction medium was stirredfor one hour and then 1ml of methyl iodide dissolved in 5ml of anhydrousether was added at 0° C. The mixture was stirred at room-temperature for12 hours and 50ml of ether were then added. The ethereal solution waswashed with a saturated solution of sodium bicarbonate, dried and thesolvent was eliminated.

In this manner, there was obtained 0.040g ofDL-8-aza-11-deoxy-15-0-methyl-PGE₁ methyl ester in the form of a paleyellow oil. Rf = 0.66.

I.R. Spectrum (CHCl₃): disappearance of OH bands.

CO (ester) at 1730 cm⁻¹,

CO (amide) at 1675 cm⁻¹.

EXAMPLE 7 Preparation ofDL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen(E)-yl)-2-pyrrolidinone or DL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ ethylester (A) Dimethyl 2-oxo-3,3-dimethyl-n-heptylphosphonate

a) 2,2-Dimethyl-hexanoic acid

In a 21-three-necked flask fitted with a dropping-funnel, a condenserequipped with a calcium chloride trap, a thermometer for low temperatureand a mechanical stirrer were introduced 650ml of anhydroustetrahydrofuran and 101g (1 mol) of diisopropylamine previously driedfor 48 hours on calcium hydride. The stirring was started and themixture was cooled to -20° C. For one hour, 400ml (1 mol) of a 16%-solution of butyl lithium in hexane were added drop-by-drop undernitrogen atmosphere. The temperature of the mixture was maintained at-10° C to -12° C and 44g (0.5 mol) of isobutyric acid freshly distilledwere introduced over a period of 20 minutes. The temperature of thereaction medium rose gradually to reach 5° C at the end of the operationof addition. The temperature was then progressively increased by heatingto 50° C and this temperature was maintained for 2 hours. The mixturewas cooled to 0° C and 68.5g (0.5 mol) of butyl bromide redistilled anddried on a 4 A screen were added over a period of 20 minutes. Thereaction medium was stirred for 2 hours while being allowed to return toroom-temperature. The mixture was allowed to stand at room-temperaturefor 12 hours and then concentrated under vacuum. The residue so obtainedwas taken up in 300ml of distilled water and 100ml of hexane. Thismixture was then stirred for 10 minutes and the aqueous fraction waswashed once with 100ml of ether and then acidified with an aqueoussolution of 50%-hydrochloric acid. The aqueous phase was extracted withether and the ethereal solution was washed once with 50ml of distilledwater, dried, concentrated and distilled under reduced pressure.

In this manner, there were obtained 49.7g of 2,2-dimethylhexanoic acidin the form of a colourless liquid. Yield : 64%.

I.R. Spectrum (film) : OH at 2500-3500 cm⁻¹

CO at 1700 cm⁻¹

CH₃ at 1375 cm⁻¹.

N.M.R. Spectrum (CDCl₃): δ = 0.9 ppm (CH₃ -CH₂),

= 1.1 ppm (CH₃ -C),

= 1 to 1.7 ppm (CH₂),

= 11.5 ppm (OH).

(b) Ethyl 2,2-dimethyl-hexanoate

A mixture of 20.16g (0.14 mol) of 2,2-dimethyl-hexanoic acid, 90ml ofabsolute ethanol, 40ml of dry benzene and 0.5ml of concentratedsulphuric acid was heated under reflux with a Dean-Stark system for 72hours. The solvents were eliminated under vacuum and the residue wastaken up with methylene chloride. This organic phase was washed with asaturated aqueous solution of sodium bicarbonate and then with distilledwater to neutrality. The organic fraction was dried and concentrated.

In this manner, there were obtained 17.8g of ethyl 2,2-dimethylhexanoatein the form of a pale yellow liquid which was homogeneous in thin layerchromatography. Yield : 74%.

I.R. Spectrum (film) : CO (ester) at 1730 cm⁻¹,

CH₃ at 1375 cm⁻¹.

(c) Dimethyl 2-oxo-3,3-dimethyl-n-heptylphosphonate

While stirring under nitrogen atmosphere, 100ml of a solution of butyllithium in anhydrous ether was added drop-by-drop in a solution of 24.8gof dimethyl methylphosphonate in 160ml of anhydrous tetrahydrofuran. Thetemperature of the reaction medium was maintained between -50° C and-60° C. After 10 minutes, a solution of 13.76g (0.08 mol) of ethyl2,2-dimethyl-hexanoate in 60ml of anhydrous tetrahydrofuran was addeddrop-by-drop care being taken to maintain the temperature between -65° Cand -70° C. The mixture was stirred for 4 hours at the same temperatureand then at 0° C for 12 hours. After acidification with 10ml of aceticacid and concentration under vacuum, the mixture was extracted withether. The ethereal solution was washed several times with water, driedon sodium sulphate, and concentrated.

In this manner, there were obtained 22.5g of crude dimethyl2-oxo-3,3-dimethyl-n-heptylphosphonate in the form of a yellow liquidand 12.2g of pure colourless product, B.P. : 69°-70° C (15 mm.Hg) Yield:61%.

N.M.R. Spectrum (CDCl₃): δ = 0.9 ppm (CH₃ butyl),

= 1.15 ppm ((CH₃)₂ -C),

= 1 to 1.6 ppm (CH₂),

= 3.15 ppm (CO-CH₂ -P),

= 3.8 ppm (OCH₃).

(B)DL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone

Under nitrogen atmosphere and at room-temperature, a solution of 5g(0.02 mol) of dimethyl 2-oxo-3,3-dimethyl-n-heptylphosphonate in 10ml ofanhydrous tetrahydrofuran was added drop-by-drop to a suspension of0.192g of sodium hydride in 60ml of anhydrous tetrahydrofuran. When thesolution was limpid, a solution of 5.38g (0.02 mol) ofDL-ω-carboethoxy-1-hexyl-5-carboxaldehyde-2-pyrrolidinone in 40ml ofanhydrous tetrahydrofuran was added drop-by-drop. Stirring wasmaintained for 4 hours at 30° C. The reaction medium was acidified withacetic acid and then concentrated under reduced pressure. This residuewas taken up in methylene chloride and the organic phase was washed with100ml of water and dried. The solvent was evaporated off and theethylenic ketone was purified by chromatography on silica gel plates(merck, F.254) using a 20/80 mixture of acetone/methylene chloride aseluent (Rf = 0.77).

In this manner, there was obtained 3.9g ofDL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinonein the form of a yellow oil which was homogeneous in thin layerchromatography. Yield : 54%.

I.R. Spectrum : CO (ester) at 1735 cm⁻¹)

CO (amide and in the 15-position) at 1695 cm⁻¹

C═C at 1630 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃ butyl),

= 1.0 ppm ((CH₃)₂ -C--),

= 4.0 ppm (--COOCH₂),

= 6.5 ppm (CH═CH).

(C) DL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ ethyl ester

To a solution of 0.293g (0.001 mol) ofDL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinonein 10ml of anhydrous dimethoxyethane, previously cooled to 0° C, wereadded under nitrogen atmosphere and by small fractions, 0.070g of sodiumborohydride. Stirring was maintained for 4 hours at a temperaturebetween 3° C and 5° C and 10ml of distilled water were added followed by20ml of a 2%-solution of tartaric acid. The solution was extracted withmethylene chloride and the traces of dimethoxyethane were eliminated byseveral washings with water. The methylene chloride solution was driedand concentrated.

In this manner, there was obtained 0.200g ofDL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ ethyl ester in the form of a paleyellow liquid which was homogeneous in thin layer chromatography. Yield: 67%. Rf = 0.50.

I.R. Spectrum (film) : OH at 3420 cm⁻¹,

CO (ester) at 1735 cm⁻¹),

CO (amide + C═C) at 1670 cm⁻¹.

N.M.R. Spectrum (CDCl₃): δ = 0.9 ppm (CH₃ butyl),

= 4.1 ppm (CH₂ --OCO),

= 5.6 ppm (CH═CH).

EXAMPLE 8 Preparation ofDL-ω-carboxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-8-aza-11-deoxy-16,16-dimethyl-PGE₁

To a solution of 0.147g ofDL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinonein 10ml of methanol were added drop-by-drop at 0° C, 5ml of 0.5N-sodiumhydroxide. The reaction medium was stirred at room-temperature for 12hours and then 20ml of water were added. The mixture was extracted withmethylene chloride and the aqueous phase was first acidified with 5ml ofHCl N and then extracted with methylene chloride. This latter solutionwas washed with water saturated with sodium chloride, dried and thesolvent was eliminated under vacuum.

In this manner, there was obtained 0.100 g ofDL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ in the form of a colourless gelwhich was homogeneous in thin layer chromatography.

Yield: 75%.

Rf = 0.20.

I.R. Spectrum (film) : OH at 3340 cm⁻¹,

COOH at 2000-3500 cm⁻¹,

COOH at 1710 cm⁻¹, CO and C═C at 1660 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃ butyl), = 5.7 ppm (CH═CH), =6.95 ppm (OH and COOH).

EXAMPLE 9 Preparation ofDL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen(E)-yl)-2-pyrrolidinoneor DL-2-methyl-8-aza-11-deoxy-PGE₁ ethyl ester (A)DL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(2'-tetrahydropyranyl-oxymethyl)-2-pyrrolidinone

A mixture of 10 g (0.05 mol) of5-(2'-tetrahydropyranyl-oxymethyl)-2-pyrrolidinone, 2 g (about 0.05 mol)of sodium amide and 200 ml of anhydrous toluene was refluxed for onehour. To this solution, 13 g of ethyl 7-bromo-2-methyl-heptanoate in 25ml of anhydrous toluene were added and the resulting mixture was heatedunder reflux for 24 hours.

The reaction medium was allowed to return to room-temperature and thenpoured into 100 ml of iced water. The mixture was decanted and theorganic phase was washed once with water saturated with sodium chloride.The aqueous phase was extracted with 50 ml of methylene chloride andthis last solution was washed once with water saturated with sodiumchloride. The toluene and methylene chloride solutions were collected,dried and concentrated.

In this manner, there were obtained 15 g ofDL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(2'-tetrahydropyranyl-oxymethyl)-2-pyrrolidinonein the form of an oil. Yield: 81%. Rf = 0.50.

N.M.R. Spectrum (CDCl₃) : δ = 1.1 ppm (CH₃ -CH),

= 1.3 ppm (CH₃ --CH₂ O),

= 4.15 ppm (--CH₂ O--),

= 4.6 ppm (O--CH--O).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared:

CompoundDL-1-(6'-carboethoxy-2'-methyl-hexyl)-5-(2'-tetrahydropyranyloxymethyl)-2-pyrrolidinone

Rf = 0.58.

I.R. Spectrum (CHCl₃) : CO (ester) at 1720 cm⁻¹,

CO (amide) at 1665 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH₂ --),= 1.3 to 2.1 ppm (CH₂ --CH, 19P), = 3 to 4 ppm (CH₂ --OCH, 17P), = 4.15ppm (CH₂ O), = 4.65 ppm (CH--O).

DL-1-(6'-carboethoxy-3'-methyl-hexyl)-5-(2'-tetrahydropyranyloxymethyl)-2-pyrrolidinone

Rf = 0.5.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH₂ --) =4.15 ppm (CH₂ O--CO), = 4.6 ppm (CH--O).

(B)DL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-hydroxymethyl-2-pyrrolidinone

A solution of 12.3 g (0.033 mol) ofDL-1-(6'-carboethoxy-6'-methylhexyl)-5-(2'-tetrahydropyranyl-oxymethyl)-2-pyrrolidinone,50 ml of ethanol and 50 ml of HCl 1N was stirred at room-temperature for12 hours. The reaction medium was concentrated under vacuum to half itsvolume and then extracted with methylene chloride. The solution soobtained was washed with distilled water, dried and concentrated.

In this manner, there were obtained 7.5 g ofDL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-hydroxymethyl-2-pyrrolidinone inthe form of a pale yellow oil.

Yield: 79%.

Rf = 0.25.

I.R. Spectrum (film) : OH at 3400 cm⁻¹, CO (ester) at 1730cm⁻¹, CO(amide) at 1670 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 1.1 ppm (CH₃ --CH₂), = 1.2 ppm (CH₃--CH--) = 2.25 ppm (OH), = 4.1 ppm (--CH₂ --O--CO).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared:

CompoundDL-1-(6'-carboethoxy-2'-methyl-hexyl)-5-hydroxymethyl-2-pyrrolidinone

Rf = 0.25.

I.R. Spectrum (film) : OH at 3400 cm⁻¹, CO (ester) at 1730 cm⁻¹, CO(amide) at 1670 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH--), =2.25 ppm (OH), = 4.15 ppm (--CH₂ --O--CO).

DL-1-(6'-carboethoxy-3'-methyl-hexyl)-5-hydroxymethyl-2-pyrrolidinone

Rf = 0.24.

Yield: 70%.

I.R. Spectrum (film): OH at 3400 cm⁻¹.

N.M.R. spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH₂ --),= 2.25 ppm (OH), = 4.15 ppm (--CH₂ --O--CO).

(C)DL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-carboxaldehyde-2-pyrrolidinone

To a mixture of 5.7 g (0.02 mol) ofDL-1-(6'-carboethoxy-6'-methylhexyl)-5-hydroxymethyl-2-pyrrolidinone,12.4 g of dicyclohexylcarbodiimide, 60 ml of anhydrousdimethylsulphoxide and 120 ml of anhydrous benzene stirred undernitrogen atmosphere and cooled to 0° C was added drop-by-drop 1.06 ml ofdichloroacetic acid. The reaction medium was stirred at roomtemperaturefor 12 hours. After that, 4.4 g of oxalic acid were added by smallfractions and 0° C. Stirring was maintained for 30 minutes and themixture was then filtered. The precipitate was washed with benzene andthe filtrate was diluted to 300 ml with chloroform. The solution waswashed with a saturated solution of sodium bicarbonate and then severaltimes with distilled water. After drying, the solvents were eliminatedunder vacuum and the residue was taken up in 50 ml of ether. Thesolution so obtained was allowed to stand for 10 minutes, filtered andthe filtrate was concentrated under vacuum. These latter operations wereeffected three times with a view to eliminating the precipitate which isonly slightly soluble in ether.

In this manner, there were obtained 5 g ofDL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-carboxaldehyde-2-pyrrolidinone.

Rf = 0.34.

I.R. Spectrum (film) : OH (weak enol) at 3300 cm⁻¹, CO (ester) at 1735cm⁻¹, CO (amide and aldehyde) at 1690 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 1.1 ppm (CH₃ --CH--), = 1.2 ppm (CH₃--CH₂), = 4.15 ppm (CH₂ O--CO), = 9.6 ppm (CHO).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared.

CompoundDL-1-(6'-carboethoxy-2'-methyl-hexyl)-5-carboxaldehyde-2-pyrrolidinone

Rf = 0.35.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH₂ --),= 4.15 ppm (CH₂ O--CO), = 9.6 ppm (CHO).

DL-1-(6'-carboethoxy-3'-methyl-hexyl)-5-carboxaldehyde-2-pyrrolidinone

Rf = 0.35.

Yield: 70%.

I.R. Spectrum (CHCl₃): OH (weak enol) at 3300 cm⁻¹, CO (ester) at 1730cm⁻¹, CO (amide and aldehyde) at 1670 cm⁻¹.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.25 ppm (CH₃ --CH₂ --),= 4.15 ppm (CH₂ O--CO), = 9.6 ppm (CHO).

(D)DL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(3'-oxo-1'-octen(E)-yl)-2-pyrrolidinone

A mixture of 2.83 g (0.01 mol) ofDL-1-(6'carboethoxy-6'-methylhexyl)-5-carboxaldehyde-2-pyrrolidinone,3.54 g of triphenylphosphoranylidene-2-heptanone, 60 ml of anhydrousdioxane and 120 ml of anhydrous benzene was refluxed for 12 hours. Thereaction medium was concentrated under vacuum and the residual oil wastaken up in 20 ml of ether. The solution was filtered, the solvent waselminated and the residue was purified by chromatography on silica gelplates.

In this manner, there was obtainedDL-1-(6'-carboethoxy-6'-methylhexyl)-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinonein the form of a pale yellow oil.

Yield: 63%.

Rf = 0.75.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃), = 1.1 ppm (CH₃ --CH--), =1.2 ppm (CH₃ CH₂ --O) = 4.1 ppm (CH₂ --O--), about 5.9 to 6.7 ppm(CH═CH).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared:

CompoundDL-1-(6'-carboethoxy-2'-methyl-hexyl)-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone

Rf = 0.78.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃, 6P), = 1.75 ppm (CH₃ ester),= 4.15 ppm (--CH₂ --O), = 5.8 to 6.5 ppm (CH═CH).

DL-1-(6'-carboethoxy-3'-methyl-hexyl)-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone

Rf = 0.77.

N.M.R. Spectrum (CDCl₃) : δ = 0.9 ppm (CH₃, 6P), = 1.25 ppm (CH₃ --CH₂),=4.15 ppm (CH₂ --O), = 6 to 6.5 ppm (CH═CH).

(E) DL-2-methyl-8-aza-11-deoxy-PGE₁ ethyl ester

A solution of 0.379 g (0.001 mol) of DL-1-(6'-carboethoxy-6'-methylhexyl-5-(3'-oxo-1'-octen-(E)-yl)-2-pyrrolidinone in 10 ml of anhydrousdimethoxyethane was cooled to 0° C. To this solution, 0.090 g of sodiumborohydride was added by small fractions. The mixture was allowed toreact at 3° C for 3 hours and then 5 ml of water followed by 5 ml of a2%-aqueous solution of tartaric acid were added with precautions. Afterextraction with methylene chloride, the solution so obtained was washedwith water saturated with sodium chloride, dried and concentrated undervacuum. The residue so obtained was chromatographed on a silica gelcolumn and a first elution was carried out with ether in order toeliminate the impurities, followed by a second elution with a 20/80acetone/methylene chloride mixture.

In this manner, there was obtained 0.250 g ofDL-2-methyl-8-aza-11-deoxy-PGE₁ ethyl ester in the form of a pale yellowoil which was homogeneous in thin layer chromatography. Yield: 65%. Rf =0.40.

I.R. Spectrum (CHCl₃):OH at 3520 cm⁻¹,

CO (ester) at 1720 cm⁻¹,

CO (amide) at 1665 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃),

about 1.1 ppm (CH₃ --CH) and (CH₃ --CH₂ O),

= 4.15 ppm (CH₂ --O),

= 5.65 ppm (CH═CH).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared:

Compound DL-6-methyl-8-aza-11-deoxy-PGE₁ ethyl ester

Rf = 0.42.

I.R. Spectrum (CHCl₃):OH at 3525 cm⁻¹,

CO (ester) at 1720 cm⁻¹,

CO (amide) at 1668 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃, 6P),

= 1.25 ppm (CH₃ ester),

= 4.15 ppm (CH₂ --O),

= 5.65 ppm (CH═CH).

DL-5-methyl-8-aza-11-deoxy-PGE₁ ethyl ester

Rf = 0.40.

Yield:78%.

I.R. Spectrum (CHCl₃):OH at 3520 cm⁻¹,

CO (ester) at 1720 cm⁻¹,

CO (amide) at 1665 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃, 6P),

= 1.2 ppm (CH₃ --CH₂),

= 4.15 ppm (CH₂ --O),

= 5.67 ppm (CH═CH).

EXAMPLE 10 Preparation ofDL-1-(6'-carboxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneor DL-2-methyl-8-aza-11-deoxy-PGE₁

A solution of 0.190 g (0.0005 mol) ofDL-1-(6'-carboethoxy-6'-methylhexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinonein 10 ml of methanol and 10 ml of sodium hydroxide 0.5N was stirredunder nitrogen atmosphere at room-temperature for 12 hours. The reactionmedium was concentrated to half its volume and 20 ml of water wereadded. The mixture was extracted with ether and the aqueous phase wasacidified with 10 ml of hydrochloric acid 1N and then extracted withmethylene chloride. The solution so obtained was washed with water andsaturated with sodium chloride. After drying, the solvent was evaporatedoff under vacuum.

In this manner, there was obtained 0.150 g ofDL-2-methyl-8-aza-11-deoxy-PGE₁ in the form of a colourless gel whichwas homogeneous in thin layer chromatography. Yield:85%. Rf:0.13.

I.R. Spectrum (CHCl₃):OH large at 2200 to 3500 cm⁻¹,

CO (acid) at 1700cm⁻¹,

CO (amide) at 1660 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃),

= 5.65 ppm (CH═CH),

= 7.05 ppm (OH and COOH).

Following the same procedure as that described above but using theappropriate starting-products, the compounds hereunder were prepared:

Compound DL-6-methyl-8-aza-11-deoxy-PGE₁

Rf = 0.15.

I.R. Spectrum (CHCl₃):OH (large) at 2200-3500 cm⁻¹,

CO (acid) at 1700 cm⁻¹,

CO (amide) at 1660 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃, 6P),

= 5.64 ppm (CH═CH),

= 7.05 ppm (OH and COOH),

disappearance of the protons CH₃ CH₂ -- of

the ester.

DL-5-methyl-8-aza-11-deoxy-PGE₁

Rf = 0.14.

Yield: about 36%.

I.R. Spectrum (CHCl₃): OH (large) at 2210-3500 cm⁻¹,

CO (acid) at 1700 cm⁻¹,

CO (amide) at 1660 cm⁻¹.

N.M.R. Spectrum (CDCl₃):δ = 0.9 ppm (CH₃, 6P),

= 5.6 ppm (CH═CH),

= 6 ppm (OH and COOH, 2P).

EXAMPLE 11

For the particular purpose of treating affections of the respiratorytract, an aerosol was prepared in accordance with known techniquescomprising as active ingredient 2 mg ofDL-8-aza-11-deoxy-16,16-dimethyl-PGE₁ together with an inert propellantand 10 g of ethanol.

We claim: 1.DL-.omega.-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-methyl-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR15## in the form of a racemic mixture or the Disomer or L isomer. 2.DL-ω-carboethoxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR16## in the form of a racemic mixture or the Disomer or L isomer. 3.DL-ω-carboxy-1-hexyl-5-(3'-hydroxy-3'-ethyl-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR17## in the form of a racemic mixture or the Disomer or L isomer. 4.DL-ω-carboethoxy-1-hexyl-5-(3'-acetoxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR18## in the form of a racemic mixture or the Disomer or L isomer. 5.DL-ω-carboxy-1-hexyl-5-(3'-acetoxy-1'-octen-(E)-yl)-2-pyrrolidinone ofthe formula: ##STR19## in the form of a racemic mixture or the D isomeror L isomer. 6.DL-ω-carbomethoxy-1-hexyl-5-(3'-methoxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR20## in the form of a racemic mixture or the Disomer or L isomer. 7.DL-ω-carboethoxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR21## in the form of a racemic mixture or the Disomer or L isomer. 8.DL-ω-carboxy-1-hexyl-5-(4',4'-dimethyl-3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR22## in the form of a racemic mixture or the Disomer or L isomer. 9.DL-1-(6'-carboethoxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR23## in the form of a racemic mixture or the Disomer or L isomer. 10.DL-1-(6'-carboxy-6'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR24## in the form of a racemic mixture or the Disomer or L isomer. 11.DL-1-(6'-carboethoxy-2'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR25## in the form of a racemic mixture or the Disomer or L isomer. 12.DL-1-(6'-carboxy-2'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR26## in the form of a racemic mixture or the Disomer or L isomer. 13.DL-1-(6'-carboethoxy-3'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR27## in the form of a racemic mixture or the Disomer or L isomer. 14.DL-1-(6'-carboxy-3'-methyl-hexyl)-5-(3'-hydroxy-1'-octen-(E)-yl)-2-pyrrolidinoneof the formula: ##STR28## in the form of a racemic mixture or the Disomer or L isomer.